New! View global litigation for patent families

US7041694B1 - Cyclooxygenase-2 inhibition - Google Patents

Cyclooxygenase-2 inhibition Download PDF

Info

Publication number
US7041694B1
US7041694B1 US09554604 US55460400A US7041694B1 US 7041694 B1 US7041694 B1 US 7041694B1 US 09554604 US09554604 US 09554604 US 55460400 A US55460400 A US 55460400A US 7041694 B1 US7041694 B1 US 7041694B1
Authority
US
Grant status
Grant
Patent type
Prior art keywords
phenyl
methylsulfonyl
yl
cyclooxygenase
trifluoromethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US09554604
Inventor
Andrew J. Dannenberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cornell Research Foundation Inc
Original Assignee
Cornell Research Foundation Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4151,2-Diazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles

Abstract

Selective inhibitors of cyclooxygenase-2 are used to treat liver disease and in combination with anti-viral drugs to treat virus-caused liver disorders. Selective inhibitors of cyclooxygenase-2 which also inhibit the synthesis of cyclooxygenase-2 improve over the efficacy of conventional selective inhibitors of cyclooxygenase-2 in the treatment of inflammatory conditions, Alzheimer's disease and cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/US98/25206 filed Dec. 7, 1998 which claims the benefit of U.S. Provisional Application No. 60/069,955 filed Dec. 17, 1997.

TECHNICAL FIELD

One invention herein is directed to an expansion of the use of selective inhibitors of cyclooxygenase-2. A different invention herein is directed to cyclooxygenase-2 inhibitors with antioxidant properties.

BACKGROUND OF THE INVENTION

Substantial research is currently being carried out to develop selective inhibitors of cyclooxygenase-2, i.e., agents which selectively inhibit cyclooxygenase-2 in preference to cyclooxygenase-1, so as to obtain the anti-inflammatory effect of cyclooxygenase-2 inhibition without the gastrointestinal side effects, e.g., peptic ulcer disease, that occur when cyclooxygenase-1 is also inhibited. Commonly used nonsteroidal anti-inflammatory drugs inhibit both cyclooxygenase-2 and cyclooxygenase-1, and the aforementioned side effects detract from their usefulness.

The focus of the research has been on synthesis of new compounds providing selective inhibition of cyclooxygenase-2 for use for treating certain inflammatory conditions, especially arthritis. The focus has not been on developing new methods of treatment, i.e., on treating conditions not heretofore considered as appropriately treatable with cyclooxygenase-2 inhibitors. The focus has not been on developing compounds with desirable functions in addition to enzyme inhibition.

Heretofore, it was considered that cyclooxygenase inhibitors could cause liver injury and for that reason liver disease was not considered as one of the conditions that was treatable by selective inhibitors of cyclooxygenase-2.

SUMMARY OF THE INVENTION

One embodiment herein, sometimes referred to hereinafter as the first embodiment herein, is directed to a method of treating a patient with liver disease comprising administering to said patient a cyclooxygenase-2 inhibiting amount of a selective inhibitor of cyclooxygenase-2. Most liver diseases are treated with minimal success. There is no effective treatment for alcoholic liver injury. Although chronic hepatitis C affects millions of individuals, interferon therapy is effective in eradicating the virus in a relatively small percentage of patients, and in patients where the virus is not eradicated, the condition can progress to cirrhosis requiring liver transplantation. Invention in the method of treatment herein resides in the realization that the anti-inflammatory properties of selective cyclooxygenase-2 inhibitors will provide a net benefit in treating liver disease and the only effective treatment in many cases. This represents a major advance. Even considering just the ability to delay the progression of cirrhosis, the aforedescribed treatment method has enormous clinical implications.

A second embodiment herein is directed to a method of treating a patient with a virus-caused liver disease comprising administering to said patient a cyclooxygenase-2 inhibiting amount of a selective inhibitor of cyclooxygenase-2 and therapeutic amount(s) of anti-viral drug(s) where the cyclooxygenase-2 inhibitor is an adjunct to anti-viral therapy to increase the effectiveness thereof. In this embodiment, the treatment with a selective inhibitor of cyclooxygenase-2 is considered to cause a decrease in the synthesis of immunosuppressive eicosanoids, thereby augmenting anti-viral therapy.

A third embodiment herein is directed to selective inhibitor of cyclooxygenase-2 which directly inhibits the enzyme cyclooxygenase-2 and which also inhibits the synthesis of the cyclooxygenase-2 protein and which has antioxidant properties.

The term “selective inhibitor of cyclooxygenase-2” is used herein to mean compound which selectively inhibits cyclooxygenase-2 in preference to cyclooxygenase-1 and particularly compound for which the ratio of the IC50 concentration (concentration inhibiting 50% of activity) for cyclooxygenase-1 to the IC50 concentration for cyclooxygenase-2 is greater than 1. Such ratio is readily determined by assaying for cyclooxygenase-2 activity and assaying for cyclooxygenase-1 activity by the methods set forth at column 39, line 55—column 40, line 36 of Talley et al. U.S. Pat. No. 5,633,272, which is incorporated herein by reference, and from the resulting data obtaining a ratio of IC50s.

DETAILED DESCRIPTION

We turn now to the embodiment herein directed to a method of treating a patient with a liver disease comprising administering to said patient a cyclooxygenase-2 inhibiting amount of a selective inhibitor of cyclooxygenase-2.

The liver diseases treated herein comprise inflammatory liver disorders and include, for example, chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver injury, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis, and liver transplant rejection.

The selective inhibitors of cyclooxygenase-2 are preferably those where the ratio of the IC50 concentration for cyclooxygenase-1 to the IC50 concentration for cyclooxygenase-2 is 5 or more, very preferably 100 or more.

Selective inhibitors of cyclooxygenase-2 include the following compounds:

  • (1) 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (2) 4-[5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (3) 4-[5-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (4) 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (5) 4-[5-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (6) 4-[5-(4-Trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (7) 4-[5-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (8) 4-[5-Phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (9) 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (10) 4-[5-(4-Trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (11) 4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (12) 4-[5-(4-Chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (13) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxylate
  • (14) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxamide
  • (15) 4-[5-(4-[Methylthio]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (16) 4-[5-(4-[Methylsulfonyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (17) 4-[5-(2,4-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (18) 4-[5-(2,6-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (19) 4-[5-(4-Cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (20) 4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (21) 4-[5-(4-Chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (22) 4-[5-(4-Chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (23) 4-[5-(4-Biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (24) 4-[5-(4-Pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (25) 4-[5-(5-Chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (26) 4-[5-(4-Morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (27) 4-[5-(1-Cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (28) 4-[5-(5-Bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (29) 4-[5-(4-Thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (30) 4-[5-(4-[Trifluoromethyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (31) 4-[5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (32) 4-[5-(2,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (33) 4-[5-Phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (34) 4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • (35) 4-[4-(Aminosulfonyl)phenyl]-5-(4-fluorophenyl) 1H-pyrazole]-3-propanoic acid
  • (36) 4,5-Dihydro-4-[3-trifluoromethyl]-1H-benz[g]indazol-1-yl]benzenesulfonamide
  • (37) 4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide
  • (38) 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide
  • (39) 4-[1-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide
  • (40) 1-(2,4,6-Trichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid
  • (41) 1-(2,6-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid
  • (42) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene
  • (43) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene
  • (44) 3-(4-(Amino sulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene
  • (45) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene
  • (46) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylic acid
  • (47) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole
  • (48) 2-(4-Fluorophenyl)-3-(4-methylsulfonyl)phenyl)-2-cyclopenten-1-one
  • (49) 4-(4-(Methylsulfonyl)phenyl-5-(4-fluorophenyl)-isothiazole
  • (50) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl-2-(5H)-furanone
  • (51) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
  • (52) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-furanone
  • (53) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl-phenyl)-2-(5H)-furanone
  • (54) 2-((4-Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene
  • (55) 3-(2,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (56) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (57) 3-(2,6-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (58) 3-(2,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (59) 3-(3,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (60) 3-(4-Bromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (61) 3-(4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (62) 3-(4-Methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (63) 3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (64) 3-(2-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (65) 3-(2-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (66) 3-(2-Bromo-4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (67) 3-(4-Chloro-2-fluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone
  • (68) 3-(3-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (69) 3-(3-Chlorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone
  • (70) 3-(2-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone
  • (71) 3-(2,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (72) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (73) 3-(2,6-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (74) 3-(3-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (75) 3-(4-Trifluoromethylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (76) 3-(3-Fluoro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (77) 3-(3-Chloro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (78) 3-(3-Bromo-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (79) 3-(2-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (80) 3-(4-Methylthiophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (81) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H-furanone
  • (82) 3-(2-Chloro-6-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (83) 3-(3-Bromo-4-methylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (84) 3-(4-Bromo-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (85) 3-(3,4-Dibromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (86) 3-(4-Chloro-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (87) 3-(4-Bromo-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (88) 3-(4-Bromo-2-chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (89) 3-(2-Naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (90) 3-(7-Quinolinyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
  • (91) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
  • (92) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
  • (93) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
  • (94) 3-(3-Bromo-4-methoxyphenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
  • (95) 3-(4-(Methylsulfonyl)phenyl)-2-phenylbenzo[b]furan
  • (96) 3-(4-Methylsulfonyl)phenyl)-2-phenylbenzo[b]thiophene
  • (97) 3-(4-Methylsulfonyl)phenyl-2-phenylinden-1-one
  • (98) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)indole
  • (99) 3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)indole
  • (100) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
  • (101) 2-(3,4-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
  • (102) 2-(4-Fluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
  • (103) 2-(3,4-Difluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
  • (104) 3-(4-(Methylsulfonyl)phenyl)-2-phenyl)-4,7-dihydrothieno[2,3-c]pyran-5-one
  • (105) 2-(4-(Methylsulfonyl)phenyl)-3-phenyl)-4H-thieno[2,3-c]furan-6-one
  • (106) 5-(4-(Methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
  • (107) 2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
  • (108) 3-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
  • (109) 2-Bromo-5-(4-(methylsulfonylphenyl)-6-phenylimidazo[2,1-b]thiazole
  • (110) 3-Trifluoromethyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
  • (111) 2,3-Dimethyl-5-(4-(methylsulfonyl)phenyl)-6-phenyl-imidazo[2,1-b]thiazole
  • (112) 5-(4-(Methylsulfonyl)phenyl)-6-(4-fluorophenyl) imidazo[2,1-b]thiazole
  • (113) 5-Phenyl)-6-(4-(methylsulfonyl)phenyl)-imidazo[2,1-b]thiazole
  • (114) 2-Chloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophen-yl)imidazo[2,1-b]thiazole
  • (115) 2,2-Dichloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophenyl)imidazo[2,1-b]thiazole
  • (116) 5-(4-(Methylsulfonyl)phenyl)-6-(imidazo[2,1-b]-1,3,4-thiadiazole
  • (117) 5-Phenyl-6-(4-(methylsulfonyl)phenyl)-imidazo[2,1-b]-1,3,4-thiadiazole
  • (118) 2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazole
  • (119) 2-Methyl-5-phenyl-6-(4-methylsulfonyl)phenyl)-imidazo[2,1-b]-1,3,4-thiadiazole
  • (120) 5-(4-(Methylsulfonyl)phenyl)-6-(4-fluorophenyl)-imidazo[2,1-b]-1,3,4-thiadiazole
  • (121) 5-(4-(Methylsulfonyl)phenyl)-6-phenyl-1H-imidazo[2,1-b]-s-triazole
  • (122) 5-Phenyl-6-(4-(methylsulfonyl)phenyl)thiazolo[3,2-b]-1,3,4-triazole
  • (123) 2,3-Dihydro-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
  • (124) 2-[(4-Methylthio)phenyl]-1-biphenyl
  • (125) 1-Cyclohexene-2-(4′-methylsulfonylphenyl)benzene
  • (126) 3-(4′-Methylsulfonylphenyl)-4-phenylphenol
  • (127) 1-[2-(4-Methylsulfonylphenyl)phenyl]piperidine
  • (128) 1-[2-(4′-Methylsulfonylphenyl)phenyl]pyrrole
  • (129) 1-Phenoxy-2-(4′-methylsulfonylphenyl)benzene
  • (130) 5-(4-Fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine
  • (131) 2-Ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine
  • (132) 5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine
  • (133) 2-Bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine
  • (134) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]propanoic acid
  • (135) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]butanoic acid, sodium salt
  • (136) 2-Benzyl-3-[1-(p-bromobenzyl)-5-methoxy-2-methylindol-3-yl-propanoic acid
  • (137) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2,2-dimethylpropanoic acid
  • (138) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4-trifluorobutanoic acid, sodium salt
  • (139) trans-2-[1-(p-Bromobenzyl 5-methoxy-2-methylindol-3-yl]-cyclo-propanecarboxylic acid, sodium salt
  • (140) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-hydroxy-2-methyl propanoic acid, sodium salt
  • (141) [1-(1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-cyclopropylacetic acid, sodium salt
  • (142) trans-(+)-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]cyclopropanecarboxylic acid, sodium salt
  • (143) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylpropanoic acid and sodium salt
  • (144) 3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4-trifluorobutanoic acid and sodium salt
  • (145) syn-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylbutanoic acid
  • (146) anti-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylbutanoic acid and sodium salt
  • (147) 3-[5-(Bromo-1-(p-bromobenzyl)-2-methylindol-3-yl]butanoic acid and sodium salt
  • (148) (−)-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-butanoic acid and sodium salt
  • (149) (+)-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-butanoic acid and sodium salt
  • (150) trans-(−)-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]cyclopropanecarboxylic acid and sodium salt
  • (151) 3-[1-(p-Bromobenzyl)-2,5-dimethylindol-3-yl]propanoic acid
  • (152) 3-[5-(Bromo-1-(p-bromobenzyl)-2-methylindol-3-yl]propanoic acid
  • (153) 3-[1-(p-Bromobenzyl)-5-chloro-2-methylindol-3-yl)propanoic acid
  • (154) 3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl)-2-methylpropanoic acid
  • (155) Methyl 3-[1-(p-bromobenzyl)-5-methoxy-2-methylindol-3-yl)propanoate
  • (156) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl)-3-methylbutanoic acid
  • (157) 5-Methanesulfonamido-6-(2,4-difluorophenylthio)-1-indanone
  • (158) 5-Methanesulfonamido-6-(2,4-dichlorophenoxy)-1-indanone
  • (159) 2-(4-Chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
  • (160) 2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
  • (161) 1-(4-Fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
  • (162) 1-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
  • (163) 2-(4-Chlorophenyl)-1-[4-methylsulfonyl)phenyl]-4-methyl-1H-imidazole
  • (164) 2-(4-Chlorophenyl)-1-[4-methylsulfonyl)phenyl]-4-phenyl-1H-imidazole
  • (165) 2-(4-Chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (166) 4-(4-Bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (167) 2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(2-naphthyl)-1H-imidazole
  • (168) 2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-1H-imidazole
  • (169) 2,4-Bis(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (170) 2-(4-Chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (171) 2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (172) 2-(4-Chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (173) 2-(4-Chlorophenyl)-4-[(4-chlorophenoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (174) 2-(3-Chloro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
  • (175) 5-[1-[4-(Methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole-2-yl]-1,3-benzodioxole
  • (176) 2-(3-Fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)-phenyl-4-(trifluoromethyl)-1H-imidazole
  • (177) 2-(4-Chlorophenyl)-4-[(phenylthio)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (178) 2-(4-Chlorophenyl)-4-[(N-methyl-N-phenylamino)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (179) 2-(4-Chlorophenyl)-4-[2-quinolyl)methoxymethyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (180) 2-(4-Chlorophenyl)-4-methoxymethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
  • (181) 2-(4-Fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole
  • (182) 1-[4-(Methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole
  • (183) 2-(3-Chloro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole
  • (184) 2-(4-Methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole
  • (185) 1-[4-(Methylsulfonyl)phenyl]-2-(4-trifluoromethyl-phenyl)-4-trifluomethyl-1H-imidazole
  • (186) 4-[2-(4-Chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
  • (187) 4-[2-(3-Chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
  • (188) 3-[1-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
  • (189) 2-[1-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
  • (190) 4-[1-[4-(Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
  • (191) 2-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
  • (192) 2-Methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
  • (193) 5-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
  • (194) 4-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
  • (195) 2-Methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
  • (196) 4-[2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
  • (197) 4-[2-(6-Methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
  • (198) 3-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine
  • (199) 4-[2-(4-Methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
  • (200) 2-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene
  • (201) 3-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene
  • (202) 4-[2-(5-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
  • (203) 2-Methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene
  • (204) 4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
  • (205) 4-[2-Pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide

The synthesis of compounds 1–39 is disclosed in Talley et al. U.S. Pat. No. 5,466,823. The synthesis of compounds 40 and 41 is disclosed in Black et al. U.S. Pat. No. 5,436,265. The synthesis of compounds 42–94 is disclosed in Ducharme et al. U.S. Pat. No. 5,474,995. The synthesis of compounds 95–105 is disclosed in Prasit et al. U.S. Pat. No. 5,521,213. The synthesis of compounds 106–123 is disclosed in Gauthier et al. U.S. Pat. No. 5,552,422. The synthesis of compounds 124–129 is disclosed in Batt U.S. Pat. No. 5,593,994. The synthesis of compounds 130–133 is disclosed in Lee U.S. Pat. No. 5,596,008. The synthesis of compounds 134–156 is disclosed in Lau et al. U.S. Pat. No. 5,604,253. The synthesis of compounds 157 and 158 is disclosed in Guay et al. U.S. Pat. No. 5,604,260. The synthesis of compounds 159–205 is disclosed in Khanna et al. U.S. Pat. No. 5,616,601.

Other selective inhibitors of cyclooxygenase-2 and their synthesis are taught in Examples 2–108, 110–129, 131–150, 152, 301–312, and 401–413 of Batt et al. U.S. Pat. No. 5,593,994, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 and their synthesis are taught in Examples 1–11, 13–16, and 18–25 of Guay et al. U.S. Pat. No. 5,604,260, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 and their synthesis are taught in Examples 1–13 including Examples 1a–1p and 4a–4h of Talley et al. U.S. Pat. No. 5,633,272, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 are taught in Examples 1–131 of Lau et al. U.S. Pat. No. 5,639,780, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 are taught in Examples 1–6 of Talley et al. U.S. Pat. No. 5,643,933, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 are taught in Examples 1–4 of Lau et al. U.S. Pat. No. 5,510,368, the disclosure of which is incorporated herein by reference.

Preferred inhibitors of cyclooxygenase-2 for use herein are 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide which is compound (1) set forth above and 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide which is compound (4) set forth above; it is believed the latter compound is celicoxib (Trade name Celebrex). Another preferred selective inhibitor of cyclooxygenase-2 is vioxx which is MK-0966. Other preferred inhibitors of cyclooxygenase-2 for use in this embodiment are those described hereinafter in connection with the third embodiment herein.

The dosage of inhibitor of cyclooxygenase-2 for the method of the first embodiment herein is a cyclooxygenase-2 inhibiting amount which is a therapeutically effective amount. In general, the dosage for the first embodiment herein ranges from 0.1 to 30 mg/kg. The dosages for any particular agent will vary within said range. For compound (1) referred to above, the dosage preferably ranges from 3 to 12 mg/kg. The administration is preferably chronic treatment, i.e., carried out indefinitely.

The route of administration for the inhibitors of cyclooxygenase-2 for the first embodiment herein is preferably oral but other routes of administration, e.g., parenteral such as intravenous, are also useful.

We turn now to the second embodiment herein, which is a method of treating a patient with a virus-caused liver disease with a cyclooxygenase-2 inhibiting amount of a selective inhibitor of cyclooxygenase-2 and a therapeutic amount of an anti-viral drug where the cyclooxygenase-2 inhibitor is an adjunct to the anti-viral therapy to increase the effectiveness thereof.

For the second embodiment herein, the virus-cause liver diseases include, for example, chronic viral hepatitis B and chronic viral hepatitis C.

For the second embodiment herein, the inhibitors of cyclooxygenase-2 that are useful are the same as those for the first embodiment herein and the dosage regimen and routes of administration are the same as for the first embodiment.

The anti-viral drugs are the same as those used conventionally for the disorder treated, and the dosages and routes of administration are those conventional for the disorder treated. For example, for chronic hepatitis B, various interferons, e.g., recombinant and natural alpha interferons, are administered parenterally and for chronic hepatitis C, interferon alpha-2b is administered subcutaneously (3 MU three times a week for six months). Other anti-viral compounds for use in the second embodiment herein include, for example, acyclovir, adenine arabinoside, and ribavirin, used, for example in conventional dosages. Combinations of agents, e.g., a combination of interferon and ribavirin, may be used with the selective inhibitor of cyclooxygenase-2.

We turn now to the third embodiment herein which is directed to selective inhibitors of cyclooxygenase-2 which directly inhibit the enzyme cyclooxygenase-2 and which also inhibit the synthesis of cyclooxygenase-2 protein and which have antioxidant properties.

The cyclooxygenase-2 inhibitors for this third embodiment preferably contain phenyl group with two or more substituents selected from the group consisting of hydroxy and C1-4-alkoxy (e.g., methoxy) on the phenyl. Such compounds are embraced by generic description in various patents but no species of selective cyclooxygenase-2 inhibitor containing phenyl group with two or more hydroxy or alkoxy substituents is disclosed in any of said patents. The patents referred to are: Talley et al. U.S. Pat. No. 5,643,933; Talley et al. U.S. Pat. No. 5,633,272; Khanna et at U.S. Pat. No. 5,616,601; Lee U.S. Pat. No. 5,596,008; Batt et al. U.S. Pat. No. 5,593,994; and Adams et al. U.S. Pat. No. 5,593,992.

Specific compounds for the third embodiment herein include, for example, 4-[5-methyl-3-[[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide and 4-methyl-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy)methyl]oxazole and the corresponding compounds where methoxy or ethoxy replaces hydroxy. 4-[5-Methyl-3-[[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide has the structure

Figure US07041694-20060509-C00001

where R1 is methyl and R2 is NH2. 4-(Methyl)-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy)methyl]oxazole has the structure

Figure US07041694-20060509-C00002

These compounds are embraced by broad disclosure in Talley et al. U.S. Pat. No. 5,643,933 but are not specifically disclosed therein. These compounds can be made analogously to Scheme XXII in U.S. Pat. No. 5,643,933 by reacting 2,3-dihydroxybenzyl bromide, where the hydroxy groups are protected by conventional techniques (for example, as described in E. Haslam, “Protection of Phenols and Catechols”, pages 145–182 in Protective Groups in Organic Chemistry, McOmie, J. F. W., editor, Plenum Press, London (1973), with alcohol corresponding to the product sought, in the presence of base, and deprotecting, and in the case of the methoxy or ethoxy compounds with alkoxy substituents in phenyl moiety, replacing the hydroxy substituents with alkoxy. Alternatively, these compounds can be made by reacting said alcohol with mesyl chloride to yield the unstable mesylate and then reacting with appropriate trihydroxyphenol. These compounds directly inhibit the cyclooxygenase-2 enzyme and also inhibit the synthesis of cyclooxygenase-2.

The selective inhibitors of cyclooxygenase-2 for the third embodiment herein have utility as broad spectrum anti-inflammatory agents for treating inflammation and inflammation-associated disorders mediated by cyclooxygenase-2 such as arthritis, inflammatory bowel disease, diabetes, Alzheimer's disease, pancreatitis, inflammatory vascular and ocular disorders, and liver disease (as described in conjunction with the first embodiment herein). They also have utility in preventing or treating cancer. The dosages are generally those set forth for selective inhibitors of cyclooxygenase-2 in the first embodiment herein. The route of administration is preferably oral although other routes of administration, e.g., parenteral, such as intravenous, may also be used.

The selective inhibitors of cyclooxygenase-2 of the third embodiment herein have improved anti-inflammatory efficacy compared to selective inhibitors of cyclooxygenase-2 which do not inhibit the synthesis of cyclooxygenase-2 protein.

The three embodiments described above are illustrated in the following examples.

EXAMPLE I

A patient with alcoholic hepatitis is admitted to a hospital complaining of nausea and upper abdominal pain. Liver function test results are total bilirubin of 4.0 mg/dl, direct bilirubin of 3.1 mg/dl, ALT of 100 IU/L, AST of 120 IU/L and prothrombin time of 15.1 seconds.

Treatment is carried out by administration of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide at a dosage of 6 mg/kg by oral route of administration, daily.

At the end of three weeks, the nausea and upper abdominal pain have resolved. Each of the blood tests has improved.

The same result is obtained when the drug administered is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide at a dosage of 6 mg/kg by oral route of administration daily.

EXAMPLE II

The patient is a 45-year old female with new onset nausea, loss of appetite and right upper quadrant tenderness. She is noted to have elevated liver chemistries. Serologic workup is notable for positive antinuclear and antismooth muscle antibodies. She is considered to have autoimmune hepatitis. Liver biopsy is consistent with this diagnosis. Treatments with 6 mg/kg oral 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide for two months, results in resolution of symptoms. The patient is subsequently maintained on an oral dose of 6 mg/kg of the same drug.

The same result is obtained when the drug administered is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide at an oral dose of 6 mg/kg.

EXAMPLE III

A patient having symptoms of malaise, anorexia and fatigue, has persistently elevated liver function tests. A blood test confirms the diagnosis of chronic viral hepatitis C.

The patient is treated by oral administration of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide at a dose of 6 mg/kg, daily for 12 months and also with subcutaneous interferon alpha-2b at a dose of 3 MU three times a week for six months, resulting in sustained normalization of liver enzymes.

The same result is obtained when the cyclooxygenase-2 inhibitor is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide at an oral dose of 6 mg/kg and the anti-viral drug is subcutaneous interferon alpha-2b at a dose of 3 Mu three times a week for six months.

EXAMPLE IV

Figure US07041694-20060509-C00003

where R1 is methyl and R2 is NH2 is reacted with 2,3-dihydroxybenzylbromide where the hydroxyls are protected, under basic conditions (K2CO3), and then deprotecting is carried out to produce 4-[5-methyl-3-[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide. The product has the structure

Figure US07041694-20060509-C00004

where R1 is methyl and R2 is NH2. The starting material is made by the reaction to produce compound 78 in Scheme XVII depicted in Talley et al. U.S. Pat. No. 5,643,933.

Many variations of the above will be obvious to those skilled in the art. Thus, the invention is defined by the claims.

Claims (4)

1. A method of treating a patient affected with liver disease selected from the group consisting of chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver injury and nonalcoholic steatohepatitis, comprising administering to said patient a cyclooxygenase-2 inhibiting amount of a selective inhibitor of cyclooxygenase-2.
2. The method of claim 1, wherein the selective inhibitor of cyclooxygenase-2 is 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
3. The method of claim 1, wherein the selective inhibitor of cyclooxygenase-2 is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
4. The method of claim 1 wherein the selective inhibitor of cyclooxygenase-2 directly inhibits the enzyme cyclooxygenase-2 and also inhibits the synthesis of cyclooxygenase-2 protein and contains phenyl group with two or more substituents selected from the group consisting of hydroxy and C1-4-alkoxy on the phenyl group.
US09554604 1997-12-17 1998-12-07 Cyclooxygenase-2 inhibition Active 2021-10-10 US7041694B1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US6995597 true 1997-12-17 1997-12-17
US09554604 US7041694B1 (en) 1997-12-17 1998-12-07 Cyclooxygenase-2 inhibition
PCT/US1998/025206 WO1999030721A1 (en) 1997-12-17 1998-12-07 Cyclooxygenase-2 inhibition

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US09554604 US7041694B1 (en) 1997-12-17 1998-12-07 Cyclooxygenase-2 inhibition

Publications (1)

Publication Number Publication Date
US7041694B1 true US7041694B1 (en) 2006-05-09

Family

ID=36272244

Family Applications (1)

Application Number Title Priority Date Filing Date
US09554604 Active 2021-10-10 US7041694B1 (en) 1997-12-17 1998-12-07 Cyclooxygenase-2 inhibition

Country Status (1)

Country Link
US (1) US7041694B1 (en)

Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6172096B2 (en) *
US5436265A (en) 1993-11-12 1995-07-25 Merck Frosst Canada, Inc. 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents
US5466823A (en) 1993-11-30 1995-11-14 G.D. Searle & Co. Substituted pyrazolyl benzenesulfonamides
US5474995A (en) 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
US5510368A (en) 1995-05-22 1996-04-23 Merck Frosst Canada, Inc. N-benzyl-3-indoleacetic acids as antiinflammatory drugs
US5521213A (en) 1994-08-29 1996-05-28 Merck Frosst Canada, Inc. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
US5552422A (en) 1995-01-11 1996-09-03 Merck Frosst Canada, Inc. Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents
US5593994A (en) 1994-09-29 1997-01-14 The Dupont Merck Pharmaceutical Company Prostaglandin synthase inhibitors
US5593992A (en) 1993-07-16 1997-01-14 Smithkline Beecham Corporation Compounds
US5596008A (en) 1995-02-10 1997-01-21 G. D. Searle & Co. 3,4-Diaryl substituted pyridines for the treatment of inflammation
US5604260A (en) 1992-12-11 1997-02-18 Merck Frosst Canada Inc. 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
US5604253A (en) 1995-05-22 1997-02-18 Merck Frosst Canada, Inc. N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors
US5616458A (en) 1990-03-14 1997-04-01 Board Of Regents, University Of Tx System Tripterygium wilfordii hook F extracts and components, and uses thereof
US5616601A (en) 1994-07-28 1997-04-01 Gd Searle & Co 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation
US5633272A (en) 1995-02-13 1997-05-27 Talley; John J. Substituted isoxazoles for the treatment of inflammation
US5639780A (en) 1995-05-22 1997-06-17 Merck Frosst Canada, Inc. N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors
US5643933A (en) 1995-06-02 1997-07-01 G. D. Searle & Co. Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
WO1997029776A1 (en) * 1996-02-13 1997-08-21 G.D. Searle & Co. Combinations having immunosuppressive effects, containing cyclooxygenase-2-inhibitors and 5-lipoxygenase inhibitors
US6048850A (en) 1992-09-22 2000-04-11 Young; Donald A. Method of inhibiting prostaglandin synthesis in a human host
US6172096B1 (en) * 1996-02-13 2001-01-09 G. D. Searle & Co. Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene B4 receptor antagonist

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6172096B2 (en) *
US5616458A (en) 1990-03-14 1997-04-01 Board Of Regents, University Of Tx System Tripterygium wilfordii hook F extracts and components, and uses thereof
US6048850A (en) 1992-09-22 2000-04-11 Young; Donald A. Method of inhibiting prostaglandin synthesis in a human host
US5604260A (en) 1992-12-11 1997-02-18 Merck Frosst Canada Inc. 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
US5474995A (en) 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
US5593992A (en) 1993-07-16 1997-01-14 Smithkline Beecham Corporation Compounds
US5436265A (en) 1993-11-12 1995-07-25 Merck Frosst Canada, Inc. 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents
US5466823A (en) 1993-11-30 1995-11-14 G.D. Searle & Co. Substituted pyrazolyl benzenesulfonamides
US5616601A (en) 1994-07-28 1997-04-01 Gd Searle & Co 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation
US5521213A (en) 1994-08-29 1996-05-28 Merck Frosst Canada, Inc. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
US5593994A (en) 1994-09-29 1997-01-14 The Dupont Merck Pharmaceutical Company Prostaglandin synthase inhibitors
US5552422A (en) 1995-01-11 1996-09-03 Merck Frosst Canada, Inc. Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents
US5596008A (en) 1995-02-10 1997-01-21 G. D. Searle & Co. 3,4-Diaryl substituted pyridines for the treatment of inflammation
US5633272A (en) 1995-02-13 1997-05-27 Talley; John J. Substituted isoxazoles for the treatment of inflammation
US5510368A (en) 1995-05-22 1996-04-23 Merck Frosst Canada, Inc. N-benzyl-3-indoleacetic acids as antiinflammatory drugs
US5639780A (en) 1995-05-22 1997-06-17 Merck Frosst Canada, Inc. N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors
US5604253A (en) 1995-05-22 1997-02-18 Merck Frosst Canada, Inc. N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors
US5643933A (en) 1995-06-02 1997-07-01 G. D. Searle & Co. Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
WO1997029776A1 (en) * 1996-02-13 1997-08-21 G.D. Searle & Co. Combinations having immunosuppressive effects, containing cyclooxygenase-2-inhibitors and 5-lipoxygenase inhibitors
US6172096B1 (en) * 1996-02-13 2001-01-09 G. D. Searle & Co. Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene B4 receptor antagonist

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
Albrecht, C., et al., Hepatology 26, No. 4, Part 2, 333A (Abstract 818) (1997).
Branca, A., et al., Derwent Abstract of WO 9639144 A1, AN 97-042830.
Denda, A., et al., Carcinogenesis 18, 1921-1930 (1997).
Dinchuk, J. E., Nature 378, 406-409 (1995).
Haslam, E., "Protection of Phenols and Catechols" in Protective Groups in Organic Chemistry, McOmie, J. F. W., editor, Plenum Press, New York (1973).
Hurizinga et al. "Chronic Pancreatitis with Biliary Obstruction" Annals of the Royal College of Surgeons of England vol. 74 pp 119-125, 1992. *
Jeng et al. "Secondary Biliary Cirrhosis A Limiting Factor in the Treatment of Hepatolithiasis" Arch Surg vol. 124 pp. 1301-1305, 1989. *
Nanji A. A., et al., Hepatology 26(6), 1538-1543 (1997).
Nanji, A. A., et al., Gastroenterology 112, 943-951 (1997).
Penning, T. D., et al., HCAPLUS Abstract AN 1997:231026 of J. Med. Chem. 1997, 40(9), 1347-1365.
Seibert et al. CAPLUS Abstract, AN 1998:369098, 1997. *

Similar Documents

Publication Publication Date Title
US5700816A (en) Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
Meldrum Tumor necrosis factor in the heart
US6762318B2 (en) Glucagon antagonists
US6136804A (en) Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions
Restrepo et al. Itraconazole therapy in lymphangitic and cutaneous sporotrichosis
US5962478A (en) Inhibition of tumor necrosis factor α
US6384034B2 (en) Method of treating migraines and pharmaceutical compositions
US6617345B1 (en) Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor, a leukotriene B4 receptor inhibitor and a cyclosporin
US20010012851A1 (en) Nitric oxide releasing oxindole prodrugs for anagesic, anti-inflammatory and disease-modifying use
US20040147581A1 (en) Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy
US20050014729A1 (en) Method for the treatment or prevention of dermatological disorders with a cyclooxygenase-2 inhibitor alone and in combination with a dermatological treatment agent and compositions therewith
US5620999A (en) Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation
EP0270316A2 (en) Topical compositions comprising 1-substituted imidazoles and NSAIDs for treatment of acne
US6136839A (en) Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
US20050227929A1 (en) Combination therapy comprising a Cox-2 inhibitor and an antineoplastic agent
US20090227602A1 (en) Compositions and treatments for inhibiting kinase and/or hmg-coa reductase
WO2005097116A1 (en) Composition comprising a jnk inhibitor and cyclosporin
WO2003017936A2 (en) Use of dppiv inhibitors as diuretic and anti-hypertensive agents
US6342510B1 (en) Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitors and a leukotriene B4 receptor antagonist
US20120035122A1 (en) Isoxazoline derivatives as antiparasitic agents
US4555524A (en) Transdermal 2-(4-isobutylphenyl)-propionic acid medication and methods
US6589997B2 (en) Small-molecule modulators of hepatocyte growth factor/scatter factor activities
WO2005044194A2 (en) TREATMENT OR PREVENTION OF NEOPLASIA BY USE OF AN Hsp90 INHIBITOR
US20050101563A1 (en) Method and compositions for the treatment and prevention of pain and inflammation
WO2003090732A1 (en) Lxr modulators for the treatment of cardiovascular diseases

Legal Events

Date Code Title Description
AS Assignment

Owner name: CORNELL RESEARCH FOUNDATION, INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:DANNENBERG, ANDREW J.;REEL/FRAME:011023/0205

Effective date: 20000526

SULP Surcharge for late payment
FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FEPP

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.)